Substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines and their using

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

 

The present invention relates to substituted 2-thio-3,5-dicyano-4-aryl-6-aminopyridines, method of their production and use as active substances for medicinal products.

It is also an object of the present invention is the use of selective ligands of the adenosine receptor for the prevention and/or treatment of various diseases.

Adenosine, a nucleoside of adenine and D-ribose, is an endogenous factor with cell-protective activity, especially in cases of damaged cells with limited oxygen and nutrient medium, for example, during ischemia in various organs (e.g. heart and brain).

Adenosine is formed inside the cells in the synthesis of adenosine-5'-monophosphate (AMF) and S-adenosylhomocysteine as an intermediate product, however, it can be isolated from cells, and then by binding with specific receptors to perform the functions of substances similar to hormones, or mediator.

Under normal conditions the concentration of free adenosine in the extracellular space is very low. However, the extracellular concentration of adenosine increased sharply in the affected organs during ischemia or hypoxia. For example, it is known that adenosine inhibits platelet aggregation and increases blood flow in the coronary vessels of the heart. In addition, adenosine impact is there on heart rate, the distribution of the mediator and differentiation of lymphocytes.

Thanks a specified activity of adenosine, there is an increase in supply of oxygen or reduced metabolism of these bodies, which contributes to the adaptation of the metabolism of the organs to the blood supply of the organ ischemia or hypoxia.

Activity of adenosine contribute to specific receptors. Up to the present time were known subtypes A1, A2A, 2b and A3. Activity of adenosine receptors inside cells promotes information the substance of camp. In the case of binding with adenosine A2A receptors or 2b such action occurs through the activation of adenylate cyclase with a constant membrane to increase intracellular cyclic adenosine monophosphate (camp), while linking with adenosine receptors A1 or A3 by inhibition of adenylate cyclase causes a reduction of the intracellular content of camp.

In accordance with the present invention under selective ligands of the adenosine receptor," you see those substances which selectively associated with one or more subtypes of adenosine receptors and can either imitate the action of adenosine (adenosine agonists) or block the action of adenosine (antagonists of adenosine).

Perhaps the distribution of selective ligands of receptors adenusi is and in different classes depending on the selectivity of their receptors, thus, for example, ligands that selectively associated with the A1-or A2-adenosine receptor, and also, for example, ligands that selectively associated with A2A - or 2b-adenosine receptor. It is also possible ligands of the adenosine receptors, which are selectively associated with multiple subtypes of adenosine receptors, thus, for example, ligands that selectively associated with A1 or A2 but not A3-adenosine receptor.

You can define the above-mentioned selectivity of the receptors through active substances on cell lines, which by stable transfection with the corresponding cDNA explore relevant subtypes of receptors (see fact sheet ON Olah, H. Ren, J. Ostrowski, K.A. Jacobson, G.L. Stiles, "Cloning, expression, and characterization of the unique bovine A1 adenosine receptor. Studies on the ligand binding site by site by site-directed mutagenesis." in J. Biol. Chem. 267 (1992) Seiten 10764-10770, which is included in the link in full).

Determination of the activity of these substances on such cell lines may biochemical measurement of intracellular content of informational substances camp (see fact sheet K.N. Klotz, J. Hessling, J. Hegler, C. Owman, C. Kull, V.V. Fredholm, M.J. Lohse, "Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells" in Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998) Seiten 1-9, which is included in the link in full).

Ligands known from the prior art, which are called "specific League is DAMI adenosine receptor", mostly referred to as derivatives based on natural adenosine (S.-A. now und R.J. Quinn, "Adenosine receptors: new opportunities for future drugs" in Bioorganic and Medicinal Chemistry 6 (1998) Seiten 619-641). However, a significant drawback of the ligands of adenosine, known from the prior art, is that they don't actually have the properties of specific receptors, are less effective than natural adenosine, or after oral administration shows only a very small efficiency. Therefore, on the basis of the above-mentioned drawbacks of these ligands is used mainly for experimental purposes.

The present invention is the finding or obtaining compounds that exhibit a wide therapeutic range and can be used as active substances for the prevention and/or treatment of various diseases.

Especially the present invention is the finding or obtaining substances, which are preferably as selective ligands of the adenosine receptor and are suitable for the prophylaxis and/or treatment of various diseases, especially diseases of the cardiovascular system (cardiovascular diseases or inflammatory diseases, but also diseases of the genitourinary system, respiratory system, Central nervous system, diabetes (osobennostjami diabetes and cancer.

Another objective of the present invention is the finding or obtaining selective ligands of the adenosine receptor with high functional specificity for the above purposes.

Therefore, the present invention relates to compounds of General formula (I)

R1, R2, R3are the same or different and independently selected from the group of the following substituents:

hydrogen;

hydroxy;

if necessary, substituted alkyl with 1-8 carbon atoms;

if necessary, substituted aryl with 6-10 carbon atoms;

if necessary, substituted alkoxy with 1-8 carbon atoms;

-O-(CH2)n-CH=CH2where n=0, 1, or 2;

halogen;

nitro;

cyano;

-C(O)-R5;

-C(O)-NR6R7;

-NR6R7;

-NR6-CO-R8;

-O-C(O)-R8;

-SO2-NR6R7; and

-NR6-SO2R8,

and:

R5is:

hydrogen;

hydroxy;

if necessary, replaced by alkyl with 1-8 carbon atoms;

if necessary, replaced by nikolkina with 3-7 carbon atoms;

if necessary, substituted alkoxy with 1-8 carbon atoms;

if necessary, substituted aryl with 6-10 carbon atoms;

if necessary, someseni is aryloxy with 6-10 carbon atoms; or

-O-(CH2)n-[(C6-C10)-aryl], where n=1, 2, or 3,

moreover, the aryl group with 6-10 carbon atoms can be annulirovano on two neighbouring ring atoms, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

or

R5is a 5-7-membered, saturated or unsaturated heterocycle, which, in turn, can be substituted one or more times

oxopropoxy (=O);

halogen;

if necessary, replaced by alkyl with 1-8 carbon atoms;

nitro;

cyano;

hydroxy;

if necessary, substituted aryl with 6-10 carbon atoms; or alkoxy with 1-8 carbon atoms,

or

R5is, if necessary, replaced, 5-6-membered heteroaryl, which has up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, if necessary, substituted aryl with 6-10 carbon atoms, or, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

and

R6and R7are identical or different and denote hydrogen;

if necessary, substituted alkyl with 1-8 carbon atoms;

if necessary, substituted aryl with 6-10 atoms is carbon; or

if necessary, substituted 5-6-membered heteroaryl, which has up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur

or

R6and R7together with the nitrogen atom to which they are, if necessary, bound, form a 5-7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, and which, if necessary, may be one or more times, identically or differently substituted

oxopropoxy (=O);

halogen;

by alkyl with 1-8 carbon atoms;

nitro;

cyano;

hydroxy;

the aryl with 6-10 carbon atoms; or

alkoxy with 1-6 carbon atoms,

and

R8is:

hydroxy;

NR6R7where R6and R7such as defined above;

if necessary, replaced by alkyl with 1-8 carbon atoms;

alkoxy with 1-8 carbon atoms;

if necessary, substituted aryl with 6-10 carbon atoms;

aryloxy with 6-10 carbon atoms; or

-O-(CH2)n-[(C6-C10)-aryl], where n=1, 2, or 3,

and

R4is unbranched or branched alkyl with 1-8 carbon atoms or alkenyl with 2-8 carbon atoms, which, if necessary, substituted one or more times

hydroxy;

halogen;

cyano;

-C(O)-R5where R5such as op is Adelino above;

-C(O)-NR6R7where R6and R7such as defined above;

-NR6R7where R6and R7such as defined above;

-NR6-C(O)-R8where R6and R8such as defined above;

-SO2-NR6R7where R6and R7such as defined above;

-NR6-SO2-R8where R6and R8such as defined above;

-C(O)-(CH2)n-C(O)-R8where n=0-2 and R8is as defined above;

alkoxy with 1-8 carbon atoms;

if necessary, replaced aryloxy with 6-10 carbon atoms;

if necessary, substituted 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur;

if necessary, substituted aryl with 6-10 carbon atoms; or

5-7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur and which, if necessary, may be one or more times, identically or differently substituted by oxopropoxy (=O); halogen; alkyl with 1-8 carbon atoms; nitro; cyano; hydroxy; aryl with 6-10 carbon atoms; or alkoxy with 1-8 carbon atoms,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, in case you have the tee, substituted aryl with 6-10 carbon atoms,

or

R4is a 5-7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, and which, if necessary, may be one or more times, identically or differently substituted by oxopropoxy (=O); halogen; alkyl with 1-8 carbon atoms; nitro; cyano; hydroxy; aryl with 6-10 carbon atoms; or alkoxy with 1-8 carbon atoms, and

which, if necessary, can be annylirovan with two adjacent ring atoms, if necessary, substituted aryl with 6-10 carbon atoms or, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

and their tautomers, and their respective salts, hydrates and alcoholate,

however, excluding the following compounds of General formula (I), in which values of the radicals R1, R2, R3and R4following:

- R1=R2=hydrogen; R3= pair-HE; R4=-CH2-Z, where Z = cyano, C(O)-OC2H5, 4-Br-C6H4-CO, 4-n-butyl-C6H4FROM hydrogen, phenyl, C(O)-O-CH2-C6H5, C(O)-OCH3, C(O) -, 2-oxo-benzo-pyranyl-3-carbonyl, 4-CI-C6H4-CO, 3-Br-C6H4-CO, 4-C6H5-C6H4-CO, 4-CH3-C6H4- , 3,4-Cl2-C6H3- ;

- R 1=R2=hydrogen; R3= meta-HE; R4=-CH2-Z, where Z=4-Br-C6H4-NH-CO 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl-C6H4- ;

- R1=R2=hydrogen; R3= pair-O-C(O)-CH3; R4=-CH2-Z, where Z=4-CH3-C6H4-N, 2-oxo-benzopyranyl-3-carbonyl, (CH2)3-CH3, 4-C6H5-C6H4;

- R1=R2=R3=hydrogen; R4=-CH2-Z, where Z=CH3CN, 2-naphthyl;

- R1=R2=hydrogen; R3= pair-butoxy; R4=-CH2-Z, where Z=4-Cl-C6H5, C(O)-OCH3With(O)6H5CH=CH2C(O)-NH2N, 4-Br-C6H4-CO, 4-Cl-C6H4-CO, C(O)-OC2H5, C(O)-O-CH2-C6H5, 2-oxo-benzopyranyl-3-carbonyl, C(O)-NH-C6H5, cyano;

- R1=R2=hydrogen; R3= para-bromine; R4=-CH2-Z, where Z=4-Br-C6H4-CO, 4-Cl-C6H4-CO, C(O)-NH2, C(O)-OCH3, 4-Cl-C6H5, 4-Br-C6H4-NH-CO;

- R1=R2=H; R3= meta-fluorine; R4=-CH2-Z, where Z=4-Br-C6H4-CO, C(O)-NH2, C(O)-O-CH2-C6H5, cyano;

- R1=R2=hydrogen; R3= pair-chloro; R4=-CH2-Z, where Z=2-naphthyl, methyl;

- R1=R2=hydrogen; R3= pair-OCH3; R4=-CH2-Z, where Z=2-naphthyl, methyl;

- R 1=R2=hydrogen; R3= meta-NO2; R4=-CH2-Z, where Z = methyl.

The above substances in accordance with the present invention can be used for the prevention and/or treatment of diseases, are partly new, but also partly known in the literature (see Dyachenko et al., Russian Journal of Chemisrty, Vol. 33, No. 7, 1997, Seiten 1014-1017 und Vol. 34, No. 4, 1998, Seiten 557-563; Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34, 1998, Seiten 188-194; EInagdi et al., Zeitschrift für Naturforschung, Vol. 47b, 1992, Seiten 572-578; Riguera et al., Eur. J.Med. Chem. 33, 1998, Seiten 887-897; J. Va-quero, Thesis, University of Alcala de Henares, Madrid, Spain, 1981). However, to date the literature has not been described therapeutic use of known compounds. In the framework of the present invention first described therapeutic use of these compounds.

Therefore, an object of the present invention is also the use of the above compounds of General formula (I), namely including the excluded above compounds for the prevention and/or treatment of diseases.

Compounds of General formula (I) depending on the substituents may be stereoisomeric forms, which are the image and mirror image (enantiomers) or are not the image and mirror image (diastereomers). This invention relates both to the enantiomers or diastereomers and their compliance is adequate mixtures. Racemic forms are also suitable for the separation of diastereomers at stereoisomeric homogeneous components in a known manner. Similarly, the invention also applies to other tautomers of the compounds of formula (I) and their salts.

Physiologically acceptable salts of the compounds of formula (I) may be salts proposed in accordance with the present invention substances with mineral acids, carboxylic acids or sulphonic acids. Most preferred, for example, are salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, triperoxonane acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Suitable salts can be salts of customary bases, such as alkali metal salts (e.g. sodium or potassium), salts of alkaline earth metals (e.g. calcium salts or magnesium), or ammonium salts derived from ammonia or organic amines, such as diethylamine, triethylamine, ethyldiethanolamine, novocaine, dibenzylamine, N-methylmorpholine is, dehydroabietylamine, 1-fenamin or methylpiperidin.

Definitions within the context of the present invention

halogen is generally fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, most preferably fluorine or chlorine.

- alkyl with 1-8 carbon atoms, alkyl with 1-6 carbon atoms or alkyl with 1-4 carbon atoms in the framework of the present invention is unbranched or branched alkyl. Examples are:

is methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-pentyl, out-of pentyl, n-hexyl, ISO-hexyl, n-heptyl and n-octyl. Preferred is unbranched or branched alkyl having 1-6 volumes of carbon. Most preferred is unbranched or branched alkyl having 1-4 carbon atoms.

- If necessary, substituted alkyl with 1-8 carbon atoms, alkyl with 1-6 carbon atoms or alkyl with 1-4 carbon atoms, such definition is used in the present invention, is videopreteen unbranched or branched alkyl, which may be one or more times, identically or differently substituted. Moreover, the substituents may be the following compounds: halogen (fluorine, chlorine, bromine, iodine); cyano; nitro; carboxy; hydroxy; an unbranched or branched alkoxy with 1-8 carbon atoms, preference is sustained fashion alkoxy with 1-6 carbon atoms, most preferably alkoxy with 1-4 carbon atoms, and alkoxy, and, if necessary, may be substituted; an unbranched or branched alkenyl with 2-8 carbon atoms, preferably of alkenyl with 2-6 carbon atoms, most preferably of alkenyl with 2-4 carbon atoms, and alkenyl, if necessary, may be substituted; aryl with 6-10 carbon atoms, especially phenyl or naphthyl, the aryl with 6-10 carbon atoms, if necessary, may be substituted; and (C1-C4)-alkylsulfonate, and (C1-C4)-alkylsulfonate, if necessary, may be substituted; phenylsulfonyl or p-tamilselvan; unbranched or branched thioalkyl with 1-6 carbon atoms, and thioalkyl, if necessary, may be substituted; an unbranched or branched monohalogen-(C1-C8)-alkyl, dihalogen-(C1-C8)-alkyl and/or trihalogen-(C1-C8)-alkyl, especially trifluoromethyl; unbranched or branched monohalogen-(C1-C8)-alkoxy, dihalogen-(C1-C8)-alkoxy and/or trihalogen-(C1-C8)-alkoxy, especially triptoreline; acyl; amino; N-[(C1-C8)-alkyl]-amino and/or N-di-[(C1-C8)-alkyl]-amino, and alkyl, if necessary, may be substituted; and (C1-C8)-arcoxia boil, alkoxycarbonyl, if necessary, may be substituted.

Aryl with 6-10 carbon atoms in the framework of the present invention is an aromatic radical. The preferred aryl radicals are phenyl and naphthyl.

- If necessary, substituted aryl with 6-10 carbon atoms in the framework of the present invention is videopreteen aromatic radical, which, if necessary, may be one or more times, identically or differently substituted, preferably by halogen (fluorine, chlorine, bromine, iodine); cyano; nitro; carboxyla; hydroxy; an unbranched or branched alkyl with 1-6 carbon atoms, preferably an alkyl with 1-6 carbon atoms, most preferably an alkyl with 1-4 carbon atoms, and alkyl, if necessary, may be substituted; an unbranched or branched alkoxy with 1 to 8 atoms carbon, preferably alkoxy with 1-6 carbon atoms, most preferably alkoxy with 1-4 carbon atoms, and alkoxy, and, if necessary, may be substituted; an unbranched or branched alkenyl with 2-8 carbon atoms, preferably alkenyl with 2-6 carbon atoms, most preferably alkenyl with 2-4 carbon atoms, and alkenyl, if necessary, may be substituted; an unbranched or branched, tioa the kilometres with 1-8 carbon atoms, thioalkyl, if necessary, may be substituted; an unbranched or branched monohalogen-(C1-C8)-alkyl, dihalogen-(C1-C8)-alkyl and/or trihalogen-(C1-C8)-alkyl, especially trifluoromethyl; unbranched or branched monohalogen-(C1-C8)-alkoxy, dihalogen-(C1-C8)-alkoxy and/or trihalogen-(C1-C8)-alkoxy, especially triptoreline; acyl; amino; N-[(C1-C8)-alkyl]-amino and/or N-di-[(C1-C8)-alkyl]-amino, and alkyl, if necessary, may be substituted; N-[(C1-C6)-alkoxy]-aldimine; and (C1-C8-alkoxycarbonyl, and alkoxycarbonyl, if necessary, may be substituted; and aryl with 6-10 carbon atoms, especially phenyl or naphthyl, the aryl with 6-10 carbon atoms, if necessary, may be substituted.

- Aryloxy with 6-10 carbon atoms is a group-O-aryl with 6-10 carbon atoms, especially a group-O-phenyl or-O-naphthyl, and the rest of the possible reference to the above definition of aryl with 6-10 carbon atoms.

- If necessary, substituted (C6-C10)-aryloxy with 6-10 carbon atoms is defined above, a group-O-aryl with 6-10 carbon atoms, with respect to the substituents of the aryl group with 6-10 atoms of plastics technology : turning & the Yes possible reference to the above definition, if necessary, a substituted aryl with 6-10 carbon atoms.

- Alkoxy with 1-8 carbon atoms, alkoxy with 1-6 carbon atoms or alkoxy with 1-4 carbon atoms, which is used in the present invention and also in the definitions (C1-C8)-alkoxycarbonyl is unbranched or branched alkoxy radical. Examples are: methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, tert-butoxy, n-pentox, out-pentox, n-hexose, out-hexose, n-heptose and n-actoxy. Preferred is an unbranched or branched alkoxy having 1-6 carbon atoms. Most preferred is an unbranched or branched alkoxy having 1-4 carbon atoms.

- If necessary, substituted alkoxy with 1-8 carbon atoms. alkoxy with 1-6 carbon atoms or alkoxy with 1-4 carbon atoms, in the framework of the present invention is videopreteen unbranched or branched alkoxy, which, if necessary, may be one or more times, identically or differently substituted, preferably by the following substituents: halogen (fluorine, chlorine, bromine, iodine); cyano; nitro; carboxyla; hydroxy; an unbranched or branched alkenyl with 2-8 carbon atoms, preferably alkenyl with 2-6 carbon atoms, most preferred is entrusted by alkenyl with 2-4 carbon atoms, and alkenyl, if necessary, may be substituted; an unbranched or branched thioalkyl with 1-8 carbon atoms, and thioalkyl, if necessary, may be substituted; an unbranched or branched monohalogen-(C1-C8)-alkyl, dihalogen-(C1-C8)-alkyl and/or trihalogen-(C1-C8)-alkyl, especially trifluoromethyl; unbranched or branched monohalogen-(C1-C8)-alkoxy, dihalogen-(C1-C8)-alkoxy and/or trihalogen-(C1-C8)-alkoxy, especially triptoreline; acyl; amino; N-[(C1-C8)-alkyl]-amino and/or N-di-[(C1-C8)-alkyl]-amino, and alkyl, if necessary, may be substituted; or (C1-C8-alkoxycarbonyl, and alkoxycarbonyl, if necessary, may be substituted.

- Cycloalkyl with 3-7 carbon atoms in the framework of the present invention is typically a ring carbon having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

- If necessary, substituted cycloalkyl with 3-7 carbon atoms in the framework of the present invention is usually videopreteen cycloalkene with 3-7 carbon atoms, which, if necessary, may be once or several times, equal or different is a substituted, especially alkyl with 1-8 carbon atoms, preferably an alkyl with 1-6 carbon atoms, most preferably an alkyl with 1-4 carbon atoms, which again may be one or more times substituted, as defined above.

- 5-6-membered aromatic heterocycle. having up to 3 heteroatoms from the series of sulfur. nitrogen and/or oxygen, in the framework of the present invention is typically monocyclic heteroaromatic compounds that are linked by a carbon atom ring heteroaromatic compounds, if necessary, the nitrogen atom of the heteroaromatic ring compounds. Examples are: furanyl (e.g., furan-2-yl, furan-3-yl), pyrrolyl (for example, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl. Preferred are pyridyl, pyrimidyl, pyridazinyl, furanyl, imidazolyl and thiazolyl.

- If necessary, substituted 5-6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O in the framework of the present invention is usually videopreteen a heterocycle which one or more times, identically or differently may be substituted by nitro; amino; guanidino; aminocarbonyl; halogen, preferably chlorine or fluorine; if necessary, replaced by alkyl with 1-6 carbon atoms, PR is doctitle by alkyl with 1-4 carbon atoms, as defined above; or, if necessary, substituted aryl with 6-10 carbon atoms.

In the framework of the present invention, the preferred compounds are compounds of General formula (I),

in which:

R1, R2, R3are the same or different and independently from each other selected from the group of the following substituents:

hydrogen;

hydroxy;

if necessary, substituted alkyl with 1-6 carbon atoms;

if necessary, substituted phenyl or naphthyl;

if necessary, substituted alkoxy with 1 to 6 carbon atoms;

-O-(CH2)n-CH=CH2where n=1 or 2;

fluorine, chlorine, bromine;

nitro;

cyano;

-C(O)-R5;

-C(O)-NR6R7;

-NR6R7;

-NR6-C(O)-R8;

-O-C(O)-R8;

-SO2-NR6R7; and

-NR6-SO2R8,

and:

R5is:

hydrogen;

hydroxy;

if necessary, replaced by alkyl with 1-6 carbon atoms;

if necessary, replaced by cycloalkene with 3-7 carbon atoms;

if necessary, substituted alkoxy with 1-6 carbon atoms;

if necessary, substituted phenyl or naphthyl;

if necessary, replaced phenyloxy or naphthyloxy; or

-O-(CH2)n-phenyl, where n=1, 2, or 3,

and GRU is PA phenyl or naphthyl may be annulirovano with two adjacent ring atoms, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

or

R5is a 5-7-membered, saturated or unsaturated heterocycle, which, in turn, can be substituted one or more times

oxopropoxy (=O);

fluorine, chlorine, bromine;

if necessary, replaced by alkyl with 1-6 carbon atoms;

nitro;

cyano;

hydroxy;

if necessary, substituted phenyl or naphthyl;

or alkoxy with 1-6 carbon atoms,

or

R5is, if necessary, replaced, 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, if necessary, substituted phenyl or naphthyl, or, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

and

R6and R7are identical or different and denote hydrogen;

if necessary, substituted alkyl with 1-6 carbon atoms;

if necessary, substituted phenyl or naphthyl; or

if necessary, substituted 5-6-membered heteroaryl,

having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur

or

R6and R7together with the nitrogen atom, with the which they if necessary, bound, form a 5-7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur and which, if necessary, may be one or more times, identically or differently substituted

oxopropoxy (=O);

fluorine, chlorine, bromine;

by alkyl with 1-6 carbon atoms;

nitro;

cyano;

hydroxy;

the phenyl or naphthyl; or alkoxy with 1 to 6 carbon atoms,

and

R8is:

NR6R7where R6and R7such as defined above;

if necessary, replaced by alkyl with 1-6 carbon atoms;

alkoxy with 1 to 6 carbon atoms;

if necessary, substituted phenyl or naphthyl;

phenyloxy or naphthyloxy; or

-O-(CH2)n-phenyl, where n=1, 2, or 3,

and

R4is unbranched or branched alkyl with 1-6 carbon atoms or alkenyl with 2-6 carbon atoms, which, if necessary, substituted one or more times

hydroxy;

fluorine, chlorine, bromine;

cyano;

-C(O)-R5where R5is as defined above;

-C(O)-NR6R7where R6and R7such as defined above;

-NR6R7where R6and R7such as defined above;

-NR6-C(O)-R8where R6and R8such as the definition of the s above;

-SO2-NR6R7where R6and R7such as defined above;

-NR6-SO2-R8where R6and R8such as defined above;

-C(O)-(CH2)n-C(O)-R8where n = 0-2 and R8is as defined above;

alkoxy with 1-6 carbon atoms;

if necessary, replaced phenyloxy or naphthyloxy;

if necessary, substituted 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur;

if necessary, substituted phenyl or naphthyl; or a 5-7 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur and which, if necessary, may be one or more times, identically or differently substituted by oxopropoxy (=O); fluorine, chlorine, bromine; alkyl with 1-6 carbon atoms; nitro; cyano; hydroxy; phenyl or naphthyl; or alkoxy with 1-6 carbon atoms,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, if necessary, substituted phenyl or naphthyl,

or

R4is a 5-7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, and which, if necessary, may be once the do many times, identically or differently substituted by oxopropoxy (=O); fluorine, chlorine, bromine; alkyl with 1-6 carbon atoms; nitro; cyano; hydroxy; phenyl or naphthyl; or alkoxy with 1-6 carbon atoms, and which, if necessary, can be annylirovan with two adjacent ring atoms, if necessary, substituted phenyl or naphthyl or, if necessary, replaced by cycloalkyl with 4-7 carbon atoms,

and their tautomers and their respective salts, hydrates and alcoholate,

however, excluding the following compounds of General formula (I), in which values of the radicals R1, R2, R3and R4following:

- R1=R2=hydrogen; R3= pair-HE; R4=-Cl2-Z, where Z=CN, C(O)-OS2H5, 4-Br-C6H4-CO, 4-n-butyl-C6H4FROM hydrogen, phenyl, C(O)-O-CH2-C6H5, C(O)-OCH3, C(O) -, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl-C6H4-CO, 3-Br-C6H4-CO, 4-C6H5-C6H4-CO, 4-CH3-C6H4- , 3,4-Cl2-C6H3- ;

- R1= R2= hydrogen; R3= meta-HE; R4= -CH2-Z, where Z = 4-Br-C6H4-NH-CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-CI-C6H4-CO;

- R1= R2= h; R3= pair-O-C(O)-CH3; R4= -CH2-Z, where Z = 4-CH3-C6H4-CO, H, 2-oxo-benzo is Irani-3-carbonyl, (CH2)3-CH3, 4-C6H5-C6H4;

- R1= R2= R3= hydrogen; R4= -CH2-Z, where Z = methyl, cyano, 2-naphthyl;

- R1= R2= hydrogen; R3= pair-butoxy; R4= -CH2-Z, where Z = 4-Cl-C6H5, C(O)-OCH3With(O)6H5CH = CH2C(O)-NH2hydrogen, 4-Br-C6H4-CO, 4-Cl-C6H4-CO, C(O)-OS2H5, C(O)-O-CH2-C6H5, 2-oxo-benzopyranyl-3-carbonyl, C(O)-NH-C6H5, cyano;

- R1= R2= hydrogen; R3= para-bromine; R4= -CH2-Z, where Z =4-Br-C6H4-CO, 4-Cl-C6H4-CO, C(O)-NH2, C(O)-OCH3, 4-Cl-C6H5, 4-Br-C6H4-NH-CO;

- R1= R2= hydrogen; R3= meta-fluorine; R4= -CH2-Z, where Z =4-Br-C6H4-CO, C(O)-NH2, C(O)-O-CH2-C6H5, cyano;

- R1= R2= hydrogen; R3= pair-chloro; R4= -CH2-Z, where Z = 2-naphthyl, methyl;

- R1= R2= hydrogen; R3= pair-OCH3; R4= -CH2-Z, where Z = 2-naphthyl, methyl;

- R1= R2= hydrogen; R3= meta-NO2; R4= -CH2-Z, where Z = methyl.

The most preferred compounds are compounds of General formula (I),

in which:

R1, R2, R3are the same or different and independently from each other selected from the group of the following substituents:

hydrogen;

hydroxy;

if necessary, substituted alkyl with 1-4 carbon atoms;

if necessary, substituted phenyl;

if necessary, substituted alkoxy with 1-4 carbon atoms;

-O-(CH2)n-CH=CH2where n=1;

fluorine, chlorine;

nitro;

cyano;

-C(O)-R5;

-C(O)-NR6R7;

-NR6R7;

-NR6-C(O)-R8;

-O-C(O)-R8;

-SO2-NR6R7; and

-NR6-SO2R8,

and:

R5is:

hydrogen;

hydroxy;

if necessary, replaced by alkyl with 1-4 carbon atoms;

if necessary, replaced by cycloalkene with 3-7 carbon atoms;

if necessary, substituted alkoxy with 1-4 carbon atoms;

if necessary, replaced by phenyl;

if necessary, replaced phenyloxy; or

-O-(CH2)n-phenyl, where n=1,

moreover, the phenyl group may be annulirovano with two adjacent ring atoms, if necessary, replaced by cycloalkyl with 5-6 carbon atoms,

or

R5is a 5-7-membered, saturated or unsaturated heterocycle, which, in turn, can be substituted one or more times

oxopropoxy (=O);

fluorine, chlorine;

if necessary, replaced by alkyl with 1 to 4 atoms of carbon is a;

nitro;

cyano;

hydroxy;

if necessary, substituted phenyl; or

alkoxy with 1-4 carbon atoms,

or

R5is, if necessary, substituted 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, which are selected from the group furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, if necessary, substituted phenyl, or, if necessary, replaced by cycloalkyl with 5-6 carbon atoms,

and

R6and R7are identical or different and denote hydrogen;

if necessary, substituted alkyl with 1-4 carbon atoms;

if necessary, substituted phenyl, or

if necessary, substituted 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, which are selected from the group furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl,

or

R6and R7together with the nitrogen atom to which they are, if necessary, bound, form a 5-7-membered saturated or unsaturated heterocycle having up to 3 Goethe is of automob from the series nitrogen, oxygen and/or sulphur, and which, if necessary, may be one or more times, identically or differently substituted

oxopropoxy (=O);

fluorine, chlorine;

by alkyl with 1-4 carbon atoms;

nitro;

cyano;

hydroxy;

by phenyl; or

alkoxy with 1-4 carbon atoms,

and

R8is:

NR6R7where R6and R7such as defined above;

if necessary, replaced by alkyl with 1-4 carbon atoms;

alkoxy with 1-4 carbon atoms;

if necessary, replaced by phenyl;

phenyloxy; or

-O-(CH2)n-phenyl, where n=1,

and

R4is unbranched or branched alkyl with 1-4 carbon atoms or alkenyl with 2-4 carbon atoms, which, if necessary, one or more times substituted by hydroxy;

fluorine, chlorine;

cyano;

-C(O)-R5where R5is as defined above;

-C(O)-NR6R7where R6and R7such as defined above;

-NR6R7where R6and R7such as defined above;

-NR6-C(O)-R8where R6and R8such as defined above;

-SO2-NR6R7where R6and R7such as defined above;

-NR6-SO2-R8where R6and R8such as defined above;

-C(O)-(CH2)n -C(O)-R8where n=0-2 and R8is as defined above;

(C1-C4)-alkoxy;

if necessary, replaced phenyloxy;

if necessary, substituted 5-6-membered heteroaryl having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, which are selected from the group furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and pyridazinyl;

if necessary, substituted phenyl; or a 5-7 membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur and which, if necessary, may be one or more times, identically or differently substituted by oxopropoxy (=O); fluorine, chlorine; alkyl with 1-4 carbon atoms; nitro; cyano; hydroxy; phenyl; or alkoxy with 1-4 carbon atoms,

moreover, if necessary, heterocycle and the ring heteroaryl can be annelirovaniya respectively with two adjacent ring atoms, if necessary, substituted phenyl,

or

R4is a 5-7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series nitrogen, oxygen and/or sulphur, and, if necessary, one or more times, identically or differently substituted by oxopropoxy (=O); fluorine, chlorine;

by alkyl with 1-4 carbon atoms; nitro; cyano; hydroxy; penelo is; or alkoxy with 1-4 carbon atoms, and

which, if necessary, can be annylirovan with two adjacent ring atoms, if necessary, substituted phenyl, or, if necessary, replaced by cycloalkyl with 5-6 carbon atoms,

and their tautomers and their respective salts, hydrates and alcoholate,

however, excluding the following compounds of General formula (I), in which values of the radicals R1, R2, R3and R4following:

- R1= R2= hydrogen; R3= pair-HE; R4= -CH2-Z, where Z = cyano, C(O)-OC2H5, 4-Br-C6H4-CO, 4-n-butyl-C6H4FROM hydrogen, phenyl, C(O)-O-CH2-C6H5, C(O)-OCH3, C(O) -, 2-oxo-benzo-pyranyl-3-carbonyl, 4-CI-C6H4-CO, 3-Br-C6H4-CO, 4-C6H5-C6H4-CO, 4-CH3-C6H4- , 3,4-Cl2-C6H3- ;

- R1= R2= hydrogen; R3= meta-HE; R4= -CH2-Z, where Z = 4-Br-C6H4-NH-CO, 2-oxo-benzo-pyranyl-3-carbonyl, 4-Cl-C6H4- ;

- R1= R2= hydrogen; R3= pair-O-C(O)-CH3; R4= -CH2-Z, where Z = 4-CH3-C6H4WITH hydrogen, 2-oxo-benzopyranyl-3-carbonyl, (CH2)3-CH3, 4-C6H5-C6H4;

- R1= R2= R3= hydrogen; R4 = -CH2-Z, where Z = CH3, cyano;

- R1= R2= hydrogen; R3= pair-butoxy; R4= -CH2-Z, where Z = 4-Cl-C6H5, C(O)-OCH3With(O)6H5CH = CH2C(O)-NH2H, 4-Br-C6H4-CO, 4-Cl-C6H4-CO, C(O)-OC2H5, C(O)-O-CH2-C6H5, 2-oxo-benzopyranyl-3-carbonyl, C(O)-NH-C6H5, cyano;

- R1= R2= hydrogen; R3= meta-fluorine; R4= -CH2-Z, where Z =4-Br-C6H4-CO, C(O)-NH2, C(O)-O-CH2-C6H5, cyano;

- R1= R2= hydrogen; R3= pair-chloro; R4= -CH2-Z, where Z = 2-naphthyl, methyl;

- R1= R2= hydrogen; R3= pair-OCH3; R4= -CH2-Z, where Z = 2-naphthyl, methyl;

- R1= R2= hydrogen; R3= meta-NO2; R4= -CH2-Z, where Z = methyl.

In accordance with the present invention is especially preferred are compounds of General formula (I),

in which:

R1, R2, R3are the same or different and independently selected from the group of the following substituents:

hydrogen;

hydroxy;

methyl;

trifluoromethyl;

methoxy;

radicals of formula-O-CH2-CH2-OH, -O-CH2-COOH or-O-CH2CH=CH2;

fluorine, chlorine or bromine;

nitro;

cyano;

-C(O)HE or-C(O)OCH3;

-C(O)NH2;

<> amino;

NH-C(O)-CH3

-O-C(O)-CH3or-O-C(O)-C2H5;

radicals of the formula

and

-NH-SO2CH3or-NH-SO2C6H5,

and

R4is unbranched or branched alkyl with 1-4 carbon atoms, which, if necessary, one or more times substituted by hydroxy;

amino;

-C(O)OCH3;

-C(O)NH2-C(O)HNCH3, -C(O)-HNC2H5or-C(O)-HNC6H5;

-NHC(O)NH2, -NHC(O)NHCH3, -NHC(O)NHC2H5, -NHC(O)OCH3or

-NHC(O)OS2H5;

-SO2-NH2;

-NH-SO2-CH3or - NH-SO2-C2H5;

methoxy;

a phenyl which may be substituted by nitro, cyano, fluorine, methoxy, deformedarse, methoxycarbonyl or p-tolilsulfonil;

pyridium, fullam, imidazolium, benzimidazolium or thiazolium, respectively, once or twice, identically or differently can be replaced by stands, nitro or chlorine; oxadiazolyl, which can be substituted by phenyl or methoxyphenyl;

or

the radical of the formula

or

R4is allyl or 3.3-dimethylallyl,

and their tautomers and their respective salts, hydrates and alcoholate,

however, excluding the following compounds of General the formula (I), in which values of the radicals R1, R2, R3and R4following:

- R1= R2= hydrogen; R3= pair-OH; R4= -CH2-Z, where Z = hydrogen, phenyl, C(O)-OCH3;

- R1= R2= hydrogen; R3= pair-O-C(O)-CH3; R4= -CH2-Z, where Z = hydrogen;

- R1= R2= R3= hydrogen; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= meta-fluorine; R4= -CH2-Z, where Z = C(O)-NH2;

- R1= R2= hydrogen; R3= pair-chloro; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= pair-OCH3; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= meta-NO2; R4= -CH2-Z, where Z = methyl.

In accordance with the present invention completely preferred are compounds of General formula (I),

in which:

R1, R2, R3are the same or different and independently selected from the group of the following substituents:

hydrogen;

hydroxy;

methyl;

methoxy;

radicals of formula-O-CH2-CH2-OH, -O-CH2-COOH or-O-CH2CH=CH2;

fluorine or chlorine;

nitro;

cyano;

-C(O)HE or-C(O)OCH3;

-C(O)NH2;

amino;

-NH-C(O)-CH3;

-O-C(O)-CH3or-O-C(O)-C2H5;

radicals of the formula

and

-NH-SO2CH3or-NH-SO2C6H5,

and

R4is unbranched or branched alkyl with 1-4 carbon atoms, which, if necessary, one or more times substituted by hydroxy;

amino;

-C(O)OCH3;

-C(O)-NH2-C(O)-HNCH3, -C(O)-HNC2H5or-C(O)-HNC6H5;

-NHC(O)NH2, -NHC(O)NHCH3, -NHC(O)NHC2H5, -NHC(O)OCH3or-NHC(O)OC2H5;

-SO2-NH2;

-NH-SO2-CH3or - NH-SO2-C2H5;

methoxy;

-phenyl;

ortho-nitrophenyl; or

radicals of the formula

or

R4is allyl,

and their tautomers and their respective salts, hydrates and alcoholate,

however, excluding the following compounds of General formula (I), in which values of the radicals R1, R2, R3and R4following:

- R1= R2= hydrogen; R3= pair-HE; R4= -CH2-Z, where Z = hydrogen, phenyl, C(O)-OCH3;

- R1= R2= hydrogen; R3= pair-O-C(O)-CH3; R4= -CH2-Z, where Z = hydrogen;

- R1= R2= R3= hydrogen; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= meta-fluorine; R4= -CH2-Z, where Z = C(O)-NH2;

- R1= R2= hydrogen; R3 = pair-chloro; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= pair-OCH3; R4= -CH2-Z, where Z = methyl;

- R1= R2= hydrogen; R3= meta-NO2; R4= -CH2-Z, where Z = methyl.

The object of the present invention is also a method of obtaining compounds of General formula (I).

In accordance with the first variant of the proposed method of obtaining compounds of General formula (I) is conducted by way of

compounds of General formula (II)

in which values of the radical R1, R2and R3such as above,

subjected to interaction with compounds of General formula (III)

R4-X (III)

in which the value of R4such as above

and

X is a nucleophilic group (preferably halogen, especially chlorine, bromine or iodine, or mesilate, tosylate, triflate or 1-imidazolyl),

in inert solvents, if necessary, in the presence of a base.

Carrying out the above method is shown, for example, the following reaction scheme:

In that case, if in the General formula (1) R4is

the alkyl substituted by a radical-NR6-C(O)-R8, -NR6-C(O)-NR6R7, -NR6-SO2-R8,

moreover, knowledge is possible radicals R 6, R7and R8such as defined above

in accordance with a second embodiment of the proposed method is also possible alternative obtaining the compounds of General formula (I), characterized in that the first compounds of General formula (II) is subjected to interaction with 2-brometalia obtaining compounds of General formula (IV)

which are then subjected to interaction with compounds of General formula V

R9-Y (V)

in which

R9is-C(O)-R8, -C(O)-O-R8, -C(O)-NR6R7, -SO2-R8where the value of R8such as defined above

and

Y is a nucleophilic group (preferably halogen, especially chlorine, bromine or iodine, or mesilate, tosylate, triflate or 1-imidazolyl),

or

R9is R6

and

Y is a group O=C=N-,

in inert solvents, if necessary, in the presence of a base.

Carrying out the above-described second option proposed in accordance with the present invention a method is shown, for example, the following reaction scheme:

Nucleophilic group, sometimes referred to as detachable or tsepliaeva group may be introduced into the reaction separately or generated in situ by conventional means, for example, and the use, the so-called reaction Mitsunobu.

As proposed in accordance with the present invention methods as solvent suitable are all organic solvents which are inert under the reaction conditions. Suitable solvents are alcohols, such as methanol, ethanol and isopropanol, ketones, such as acetone and methyl ethyl ketone, acyclic and cyclic ethers, such as simple diethyl ether and tetrahydrofuran, esters such as ethyl ether, acetic acid or butyl ester of acetic acid, hydrocarbons, such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide (DMSO), chlorinated hydrocarbons such as dichloromethane, chlorobenzene or dichloromethane or triamide hexamethylphosphoric acid. Water is also a suitable solvent. The most preferred solvent is dimethylformamide. You can also use mixtures of the aforementioned solvents.

As suitable bases are customary inorganic or organic bases. Suitable bases are preferably alkali hydroxides such as sodium hydroxide or potassium, or alkali carbonates such as sodium carbonate or potassium, or sodium bicarbonate or potassium, or methanolate n is sodium or potassium, or ethanolic sodium or potassium, or tert-butyl potassium, as well as amides such as sodium amide, lithium bis(trimethylsilyl)amide or sitedisability, or ORGANOMETALLIC compounds such as utility or finality, and also amines, such as triethylamine and pyridine. Preferred are carbonates and bicarbonates of alkali.

The amount used of the base is 1 to 10 mol, preferably 1 to 5 mol, especially from 1 to 4 mol, relative to 1 mol of the compounds of General formula (II) or (IV).

The reaction is usually carried out at temperatures from -78°With up to temperature phlegmy, preferably in the range from -78°C to 40°With, especially at room temperature.

Carrying out transformations possible with normal, elevated or reduced pressure (for example, in the range from 0.5 to 5 bar). Usually work at normal pressure.

The person skilled in the art numerous variations of the above-mentioned conditions, which are on the level of knowledge the average specialist and not beyond the scope of this invention.

Compounds of General formula (II) are also known to the person skilled in the art or can be obtained from a conventional, well-known in the literature methods. Preferably result in the following publications, which are listed as links:

- Dyachenko et al., Russian Journal of Chemitry, Vol. 33, No. 7, 1997, Seiten 1014-1017 und Vol. 34, No. 4, 1998, Seiten 557-563;

- Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34, No. 2, 1998, Seiten 188-194;

- Qintela et al., European Journal of Medicinal Chemistry, Vol. 33, 1998, Seiten 887-897;

- Kandeel et al., Zeitschrift fur Naturforschung 42b, 107-111 (1987).

Compounds of General formula (II) can also be obtained from compounds of General formula (VI) by reacting with alkali sulfide. This method of obtaining shown, for example, the following reaction scheme:

As the alkali sulfide is preferable to use sodium sulfide in an amount of from 1 to 10 mol, preferably 1 to 5 mol, especially from 1 to 4 mol, relative to 1 mol of the compounds of General formula (VI).

The solvent suitable are all organic solvents which are inert under reaction conditions. Suitable solvents are N,N-dimethylformamide, N-methylpyrrolidinone, triamide hexamethylphosphoric acid, pyridine and acetonitrile. Most preferred is N,N-dimethylformamide. You can also use mixtures of the aforementioned solvents.

The reaction is usually carried out at temperatures from +20°With up to temperature phlegmy, preferably in the range from +20°C to +120°With, especially at +60°C to +100°C.

Conducting interaction is possible at normal, elevated or reduced pressure (for example, in the range from 0.5 to 5 bar). Usually operate at normal pressure.

The person skilled in the art numerous variations of the above-mentioned conditions, which are medium-specific knowledge and not beyond the scope of this invention.

Compounds of General formula (VI) is also known to the person skilled in the art or can be obtained from a conventional, well-known in the literature methods. Preferably indicate the publication Kambe et al. Synthesis, 531 (1981), the contents of which are incorporated by reference.

Compounds of General formula (III) or (V) or commercially available, or known to the person skilled in the art, or can be obtained in accordance with customary methods.

Unexpectedly, the compounds of General formula (I) exhibit unpredictable, with important pharmacological value range of actions and are therefore particularly suitable for the prophylaxis and/or treatment of diseases.

So, now unexpectedly found that the substance of the above formula (I) are suitable for the prophylaxis and/or treatment of various diseases, for example, especially diseases of the cardiovascular system (cardiovascular disease); diseases of the genitourinary system; respiratory diseases; inflammatory and neuropeptidergic diseases; diabetes, especially diabetes; cancer; and also neurodegenerative diseases,for example, such as Parkinson's disease and pain syndromes.

More specifically, the present invention under the diseases of the cardiovascular system or cardiovascular diseases see, for example, the following diseases: coronary heart disease; hypertension (high blood pressure); restenosis, for example restenosis after balloon dilation of peripheral blood vessels; arteriosclerosis; tachycardia; cardiac arrhythmias; peripheral and cardiac angiopathy; stable and unstable angina; atrial fibrillation.

In addition, compounds of General formula (I) are also suitable for the recovery area of the myocardium affected by a heart attack.

In addition, compounds of General formula (I) are also suitable for the treatment and prevention of thromboembolitic diseases and ischemia such as myocardial infarction, brain hemorrhage, temporary ischemic attacks.

Another indication for which are appropriate compounds of General formula (I), is the prevention and/or therapy of diseases of the genitourinary system, such as hyperesthesia of the bladder, erectile dysfunction and female sexual dysfunction, in addition, prevention and/or treatment of inflammatory diseases, such as asthma and inflammatory dermatoses, neuropeptidergic C the illnesses of the Central nervous system, for example, such as state after cerebral infarction, Alzheimer's disease, in addition, neurodegenerative diseases such as Parkinson's disease and pain syndromes.

Another indication are diseases of the respiratory tract, such as asthma, chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis (mucoviscidosis) and pulmonary hypertension.

In addition, it is possible to use compounds of General formula (I) for the prevention and/or treatment of liver fibrosis and cirrhosis.

Finally, it is possible to use compounds of General formula (I) for the prevention and/or treatment of diabetes, in particular diabetes.

Thus, the present invention also relates to uses of compounds of General formula (I) upon receipt of medicines and pharmaceutical compositions for the prevention and/or treatment of the above-mentioned pattern of diseases.

In addition, the present invention relates to a method for prevention and/or treatment of the above-mentioned pattern of diseases with the use of the substances of the General formula (I).

The pharmaceutical activity of the above compounds of General formula (I) is due to their activity as selective ligands to a single or many subtypes of adenosine receptors, particularly as selective ligands for the receptor is m adenosine-A1, adenosine-A2A and/or adenosine-2b, preferably as selective ligands for adenosine receptors, A1 and/or adenosine-2b.

In the framework of the present invention under the "selective" understand such ligands of the adenosine receptor, which, on the one hand, see a clear effect in relation to one or more subtypes of the adenosine receptor, and on the other hand, does not see or see little action in relation to one or more other subtypes of adenosine receptor, and on methods to study functional selectivity link to the research methods described in section A. II.

Substances of General formula (I) are much selective than the ligands of the adenosine receptor, known from the prior art. Thus, for example, compounds of General formula (I)in which R4is an alkyl with 1-4 carbon atoms, which is substituted by a group of the formula-C(O)NR6R7and R6and R7the same or different and are hydrogen or, if necessary, replaced by alkyl with 1-3 carbon atoms, usually selectively apply adenosine receptor-2b.

On the other hand, compounds of General formula (I)in which R4is an alkyl with 1-4 carbon atoms, which is substituted by one or more hydroxy groups, usually selectively de is there-receptor adenosine-A1.

In turn, compounds of General formula (I), R4is an alkyl with 1-4 carbon atoms, which is substituted by imidazolyl or, if necessary, substituted benzyl, usually selectively acts on receptors of adenosine A1 and adenosine-2b.

You can determine the selectivity of the receptors by biochemical measurement of intracellular contents information of the substance of camp in cells that specifically examine only one subtype of adenosine receptor. And in the case of agonists see an increase in the intracellular content of camp, and in the case of antagonists see a decrease in the intracellular content of camp after pre-stimulation with adenosine or substances such as adenosine (see publications C. Kull, G. Arslan, S. Nilsson, C. Owman, A. Lorenzen, U. Schwabe, C. C. Fredholm, "Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors", Bio-chem. Pharmacol., 57 (1999) Seiten 65-75; und S.P. Alexander, J. Cooper, J. Shine, S.J. Hill, "Characterization of the human brain putative A2B adenosine receptor expressed in Chinese hamster ovary (CHO.A2B4) cells", Br. J. Pharmacol., 119 (1996) Seiten, the contents of which are incorporated by reference).

Therefore, an object of the present invention is also the use of selective ligands of the adenosine receptor, especially selective ligands of the adenosine receptor A1, adenosine-A2A and/or adenosine-2b, upon receipt of medicines and pharmace the political compositions for the prevention and/or treatment of diseases, for example, especially diseases of the cardiovascular system (cardiovascular disease); diseases of the genitourinary system; inflammatory and neuropeptidergic diseases; neurodegenerative diseases; respiratory diseases; liver fibrosis, cirrhosis; cancer; and, finally, diabetes, especially diabetes, and relatively separate areas displays the link is also on the above statement.

Thus, compounds of General formula (I), which is selectively connected with the adenosine receptor A1, are suitable preferably for effects on the myocardium and for the prevention and/or treatment of tachycardia, atrial fibrillation, heart failure, acute renal failure, diabetes, and pain syndromes. On the other hand, compounds of General formula (I), which selectively bound to receptors of adenosine-A2A, are preferably suitable for the prophylaxis and/or treatment thromboembolitic diseases, neurodegenerative diseases such as Parkinson's disease, as well as for wound healing. In addition, compounds of General formula (I), which selectively associated with adenosine receptor-2b, are preferably suitable for the prophylaxis and/or treatment of liver fibrosis, heart attack, neuropeptidergic diseases, such as illness, Alice the measure, urinary incontinence and respiratory diseases such as asthma and chronic bronchitis.

Another object of the present invention are drugs and the pharmaceutical formulation, which contain at least one selective receptor ligand adenosine and/or adenosine-2b, preferably at least one compound of General formula (I), together with one or more pharmacologically acceptable excipients or carriers, and the method of their use for such purposes.

For the introduction of compounds of General formula (I) use all the usual forms of use, that is, oral administration, parenteral administration, inhalation, nasal application, sublingual application, pryamokishechnye introduction or external use, for example, percutaneous application, most preferably oral or parenteral application. When parenteral administration is preferred intravenous, intramuscular, subcutaneous method, for example, as a subcutaneous depot. Absolutely, it is preferable to oral administration method.

Moreover, the active substance may be issued independently or in the form of compositions. For oral administration as compositions suitable are, in particular, tablets, cap the uly, pills, pills, granules, solid or liquid aerosols, syrups, emulsions, suspensions and solutions. Moreover, the amount of the active substance must be optimal for achieving a therapeutic effect. Typically, the concentration of the active substance is from 0.1 to 100 wt.%, especially from 0.5 to 90 wt.%, preferably from 5 to 80 wt.%. The preferred concentration of the active substance should be from 0.5 to 90 wt.%, that is, the amount of the active substance should be sufficient for these opportunities dosage.

For this purpose, may become active substances in a known manner in a conventional composition. Such transformation is carried out with the use of an inert, nontoxic, pharmaceutically suitable carriers, excipients, solvents, pharmaceutical bases, emulsifiers and/or dispersing agents.

As auxiliary substances are suitable, for example, water, non-toxic organic solvents, such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers, such as natural or synthetic powdery substance from rocks (for example, talc and silicates), sugars (e.g. lactose), emulsifiers, dispersants (for example polyvinylpyrrolidone) and with ASCI (for example, magnesium sulfate).

In the case of oral administration of tablets, of course, can also contain additives such as sodium citrate, together with fillers, such as starch, gelatin and the like. In addition, for oral use water compositions can be either with additives to improve taste or dyes.

To achieve effective results when parenteral application is the preferred quantity of a drug is usually from about 0.1 to about 10000 μg/kg, preferably from about 1 to about 1000 μg/kg, especially from about 1 to about 100 μg/kg of body weight. For oral use, the quantity of a drug is from about 0.1 to about 10 mg/kg, preferably from about 0.5 to 5 mg/kg, especially from about 1 to about 4 mg/kg body weight.

Notwithstanding the foregoing, if necessary, possible deviations from the specified number, namely depending on the body weight, route of administration, the individual response to the active substance, the type of composition and the time or interval at which carry out the application.

The following examples explain in more detail the present invention, but in no way limit it, but only help to better understand the invention.

A. Analysis of physiological activity

I. confirmation of the cardiovascular on istia

Research Langendorf heart rat

In rats under anesthesia after opening the chest quickly take out the heart and put it in a conventional apparatus Langendorf. In the coronary arteries keep a constant flow (10 ml/min) and the resulting perfusion pressure is recorded by a corresponding pressure sensor. In this study, the decrease perfusing pressure corresponds to the relaxation of the coronary arteries. At the same time by using a balloon inserted into the left ventricle, and another pressure sensor measures the pressure in the ventricle that occurs during each contraction. The frequency of the isolated beating heart is determined on the basis of the calculation of the number of cuts per unit time.

In this study receive the following values coronary perfusing pressure (specified percentage value refers to the percentage of the decrease in coronary perfusing pressure at the appropriate concentration):

The percentage decrease in coronary perfusing pressure at a concentration of:
The connection formulas (1)10-7g/ml10-6g/ml
R1= R2= hydrogen

R3=PA is a-CH 3< / br>
R4= -CH2-CH(OH)(CH2OH)

(compound of example A)
No effectAbout 26%
R1= R2= hydrogen

R3= pair-CH3< / br>
R4= -CH2-phenyl (compound of example A)
No effectAbout 37%
R1= R2= hydrogen

R3= meta-HE

R4= -CH2-CH2OH (compound of example 43)
About 42%About 68%
R1= R2= hydrogen

R3= pair-HE

R4= -CH2-CH2OH (compound of example 21)
Approximately 40%About 75%
R1= R2= hydrogen

R3= pair-HE

R4= 2-imidazoline (compound of example And 379)
About 64%About 63%

Analyte these concentrations do not have steps or pressure in the left ventricle of the heart that occur during contractions, or heart rate. As a consequence, it is proved that the substance selectively affect only coronary blood flow.

II. Confirmation of receptor selectivity (selectivity of adenosine receptors A1, A2A, 2b and A3)

Cells permanent line CHO (Chinese hamster Ovary) consistently with the Ute with cDNA for subtypes of adenosine receptor A1, A2A, 2b and A3. Communication of substances with subtypes of receptor A2A or 2b determined by measuring the intracellular content of camp in these cells using conventional in vitro radioimmunoassay analysis (cAMP-RIA, IBL GmbH, Hamburg, Deutschland).

In the case of substances as agonists communication occurs substances with a decrease in the intracellular content of camp. In the case of compound comparison in these studies is used as a compound similar to adenosine NECA (5-N-ethylcarbodiimide-adenosine), which is not selectively, but with high affinity associated with all subtypes of adenosine receptors and possesses agonistic action (Klotz, K.N., Hessling, J., Hegler, J., Owman, C., Kull, B., Fredholm, B.B., Lohse, M.J., Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cell, Naunyn Schmiedeberg Arch Pharmacol, 357 (1998), 1-9).

Adenosine receptors A1 and A3 are associated with Gi protein, i.e. stimulation of these receptors leads to inhibition of adenylate cyclase and due to the lowering of the intracellular level of camp. To identify agonists of the A1/A3-recetor adenylate cyclase stimulate Forskolin. However, the additional stimulation of the A1/A3-receptors inhibits adenylate cyclase, so that agonists of the A1/A3-receptor can be determined relatively low content of cells with camp.

To confirm the antagonistic action of adenosine receptor combined, recombination the e cells pre-stimulated NECA and investigate the effect of substances on the reduction of the intracellular content of camp. In the link quality comparison in these studies used KHAS (related continuine), which is not selectively, but with high affinity associated with all subtypes of adenosine receptor and has an antagonistic effect (Muller, C.E., Stein, C., Adenosine receptor antagonists: structures and potential therapeutic applications, " Current Pharmaceutical design, 2 (1996), 501-530).

In the following studies to determine the intracellular content of camp in CHO cells, which combine with cDNA for 2b-receptor. Percentage concentration of camp in the cell deepening plate for micrometrology are relative to control values without the impact of the proposed substances:

The concentration of intracellular content of camp in percent at a concentration of:
The connection formulas (1)10-9M10-8M10-7M10-6M10-5M
NECA (comparison)36334085812261263
R1= R2= hydrogen

R3= pair-OH

R4= -CH2-C(O)NH2(compound from example A1)
837 947900
R1= R2= hydrogen

R3= pair-HE

R4= -CH2-CH2OH (compound of example 21)
253432384
R1= R2= hydrogen

R3= meta-HE

R4= -CH2-CH2OH (compound of example 43)
347674784
R1= R2= hydrogen

R3= meta-HE

R4= -CH2-CH(CH2HE (the compound of example 46)
463716753
R1= R2= hydrogen

R3= hydrogen

R4= -CH2-CH2OH (compound of example And 104)
100178438586571
R1= R2= hydrogen

R3= pair-HE

R4= 2-imidazoline (compound of example And 379)
8708468619361140

In these studies the effect of all substances blocked by non-selective but highly specific for adenosine receptor antagonists KHAS.

In the following studies describe inside the cellular content of camp in CHO cells, that combined with cDNA for A2A-receptor. Percentage concentration of camp in the cell deepening plate for micrometrology are relative to control values without the impact of the proposed substances

The concentration of intracellular content of camp in percent at a concentration of:
The connection formulas (1)10-9M10-8M10-7M10-6M10-5M
NECA (comparison)585800130119922075
R1= R = hydrogen

R3= pair-OH

R4= -CH2-C(O)NH2(compound from example A1)
92117208
R1= R2= hydrogen

R3= pair-HE

R4= -CH2-CH2OH (compound of example 21)
143117
R1= R2= hydrogen

R3= meta-HE

R4= -CH2-CH2OH (compound of example 43)
117200317
R1= R2= hydrogen

R3= meta-HE

R4= -CH2-CH(CH3HE (the compound of example 46)
67108183
R1= R2= hydrogen

R3= hydrogen

R4= -CH2-CH2OH (compound of example And 104)
104107107146212
R1= R2= hydrogen

R3= pair-HE

R4= 2-imidazoline (compound of example And 379)
93160218235291

In these studies the effect of all substances blocked by non-selective but highly specific for adenosine receptor antagonists KHAS.

In the following studies to determine the intracellular content of camp in CHO cells, which combine with cDNA for A1-receptor. Percentage concentration of camp in the cell deepening plate for micrometrology are relative to control values without the impact of the proposed substances, but after pre-stimulation of 1 μm by Forskolin for 15 min (for measurement data the content of camp without prior stimulation Forskolin 18%):

 The concentration of intracellular content of camp in percent at a concentration of:Used compound of formula (I)10-7M10-6M10-5MNECA (comparison)242428R1= R = hydrogen

R3= meta-HE

R4= -CH2-CH2OH (compound of example 43)182422R1= R2= hydrogen

R3= hydrogen

R4= -CH2-CH2OH (compound of example And 104)282321R1= R2= hydrogen

R3= pair-HE

R4= 2-imidazoline (compound of example And 379)343435

Thus, the compound of example A1 has a clear agonistic effect on cells that explore the adenosine receptor 2b, and almost no effect on the cells with the A2A receptor. On the contrary, the compounds of examples 43 and 104 have a clear agonistic effect on the cells from A1-receptor virtually no effect on the cells with the A2A-receptor and a weaker effect on cells with 2b-receptor, and thus are selective agonists of the adenosine receptor A1. On the other hand, the compound of example And 379 demonstrates a clear agonistic effect on cells with 2b-receptor virtually no effect on the cells with the A2A-receptor and a relatively weak effect on the cells from A1-receptor, and thus, is a selective agonist of the adenosine receptor 2b.

C. Examples of synthesis

Example 1

2-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}-N-methylacetamide

of 53.6 mg (0.2 mmol) 2-amino-4-(4-hydroxyphenyl)-6-effect-free remedy 3,5-Piri-indianmanatee and 45.6 mg (0.3 mmol) of N-methylpropanamide stirred in 0.5 ml of dimethylformamide (DMF) with a 33.6 mg (0.4 mmol) of NaHCO3for 4 hours at room temperature (RT). Thin layer chromatography (TX) (CH2Cl2/CH3HE 10:1) shows complete conversion. The resulting product is diluted with water and ether complex of acetic acid (HER), HER-phase is dried MgSO4and evaporated in vacuum. The residue is crystallized from methanol.

Yield: 45 mg (66.3% of theory) of white crystals.

Mass spectrum: the desired molar mass: 339, found [M+H]+=340,3.

Example 2

2-{[6-Amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}-N,N-diethylacetamide

of 53.6 mg (0.2 mmol) 2-amino-4-(4-hydroxyphenyl)-6-effect-free remedy 3.5-pyridineacetonitrile and to 58.2 mg (0.3 mmol) of N,N-delivre is the ndimethylacetamide stirred in 0.5 ml of DMF together with a 33.6 mg (0.4 mmol) of NaHCO 3for 4 hours at KT. TX control (CH2Cl2/CH3HE 10:1) shows complete conversion. The resulting product is diluted with water and ether complex of acetic acid (HER), HER-phase is dried MgSO4and evaporated in vacuum. The residue is crystallized from methanol.

Yield: 50 mg (65,5% of theory) of white crystals.

Mass spectrum: the desired molar mass: 381, found [M+H]+=382.

Example 3

2{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}-N-ethylacetamide

0,76 g (2 mmol) 2-amino-4-(4-hydroxyphenyl)-6-effect-free remedy 3,5-pyridine-carbonitrile and 0.5 g (3 mmol) of N-ethylbromoacetate stirred in 5 ml of DMF together with 0.34 g (4 mmol) of NaHCO3for 4 hours at KT. The mixture is then diluted with water and extracted with ether complex of acetic acid, the phase of ester acetic acid, dried with MgSO4and evaporated in vacuum. After evaporation the solid residue is stirred with methanol. The crystals are separated and dried in vacuum.

Output: 0,49 g (69,5% of theory) of crystals.

Mass spectrum: the desired molar mass: 353, found [M+H]+=354,2.

Example 4

2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridinedicarboxylic

268 mg (1 mmol) 2-amino-4-(4-hydroxyphenyl)-6-effect-free remedy 3,5-pyridine-dicarbonitrile, 105 mg (1 mmol) 2-bromelain-Hydrobromic the a and 168 mg (2 mmol) and NaHCO 3stirred in 1 ml of DMF for 1 hour. The resulting product is diluted with several milliliters of 1N HCI. The crystals are separated and dried in vacuum.

Yield: 200 mg (64.2% of theory) of yellow crystals.

Mass spectrum: the desired molar mass: 311, found [M+H]+=312.

Example 5

N-(2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]-sulfanyl}ethyl)-ndimethylacetamide

60 mg (0.2 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile and 30 mg (0.3 mmol) of N-acetylimidazole stirred in 0.5 ml of DMF for 1 hour at KT. Then to the mixture is slowly added dropwise water, after the occurrence of lung opacities intermediate vykristallizovyvalas, then separated, washed with water and dried in vacuum. Obtain 53 mg of yellow crystals. The crystals are dissolved in 1 ml of CH2Cl2/CH3HE (mixture 1:1) and mixed with a few drops of concentrated ammonia (remove Vallromanes cork product). The mixture is stirred for 5 hours at KT. When the concentration of the reaction solution product vykristallizovyvalas, then separated and washed with methanol.

Yield: 37 mg (52.3% of theory) of almost white crystals.

Mass spectrum: the desired molar mass: 353, found [M+H]+=354.

Example 6

2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}-methyl)-carbs is t

to 31.1 mg (0.1 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 1-2 ml of dichloromethane in the presence of argon at KT and cooled at a temperature of -20 to -25°C. Then, to the resulting mixture of 30.3 mg (0.3 mmol) of triethylamine and 28.3 mg (0.3 mmol) of a compound of methyl ether of Harborview acid at the same temperature. The mixture is additionally stirred for 30 minutes at -20°With, then allow the mixture to arrive within 1 hour at a temperature of 0°C. the Product was concentrated in vacuo, mixed with 4 ml of 2-molar solution of NH3in methanol and stirred for 1 hour at room temperature. The product is then concentrated, dissolved in 600 μl of DMSO and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 NO 5 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water +0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 600 μl of DMSO solution

Output: 21,7 mg (58.7% of theory) of the product

Mass spectrum: the desired molar mass: 369, found [M+H]+=370,1.

Example 7

2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridi the Il]sulfonyl}-ethyl)-carbamate

to 31.1 mg (0.1 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 1-2 ml of dichloromethane in the presence of argon at KT and cooled at a temperature of -20 to -25°C. Then, to the resulting mixture of 30.3 mg (0.3 mmol) of triethylamine and 32.6 mg (0.3 mmol) of a compound of methyl ether of Harborview acid at the same temperature. The mixture is additionally stirred for 30 minutes at -20°With, then allow the mixture to arrive within 1 hour at a temperature of 0°C. the Product was concentrated in vacuo, mixed with 4 ml of 2-molar solution of NH3in methanol and stirred for 1 hour at KT. The product is then concentrated, dissolved in 600 μl of DMSO and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 NO 5 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water +0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 600 μl of DMSO solution

Output: 20,5 mg (53.5% of theory) of the product

Mass spectrum: the desired molar mass: 383, found [M+H]+=384,2.

Example 8

4-[2-amino-3,5-dicyano-6-({2-[(methoxycarbonyl)amino]ethyl}sulfanyl)-4-feast of dinyl]phenyl-methylcarbonate

to 31.1 mg (0.1 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 1-2 ml of dichloromethane in the presence of argon at KT and cooled at a temperature of -20 to -25°C. Then, to the resulting mixture of 10.1 mg (0.1 mmol) of triethylamine and 9.4 mg (0.1 mmol) of a compound of methyl ether of Harborview acid at the same temperature. The mixture is additionally stirred for 30 minutes at -20°With, then allow the mixture to arrive within 1 hour at a temperature of 0°C. the product is Then concentrated, dissolved in 600 μl of DMSO and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water +0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 600 μl of DMSO solution

Output: 11.2 mg (26,2% of theory) of the product

Mass spectrum: the desired molar mass: 427, found [M+H]+=428,2.

Example 9

4-[2-amino-3,5-dicyano-6-({2-[(methoxycarbonyl)amino]ethyl}sulfanyl)-4-pyridinyl]phenyl-ethylcarbonate

to 31.1 mg (0.1 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyben is l)for 3,5-pyridineacetonitrile suspended in 1-2 ml of dichloromethane in the presence of argon at KT and cooled at a temperature of -20 to -25° C. Then, to the resulting mixture of 10.1 mg (0.1 mmol) of triethylamine and 10.9 mg (0.1 mmol) of a compound of methyl ether of Harborview acid at the same temperature. The mixture is additionally stirred for 30 minutes at -20°With, then allow the mixture to arrive within 1 hour at a temperature of 0°C. the product is Then concentrated, dissolved in 600 μl of DMSO and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 600 μl of DMSO solution

Output: 15,2 mg (33.4% in theory) of the product

Mass spectrum: the desired molar mass: 455, found [M+H]+=456,2.

Example 10

N-(2{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}ethyl)-urea

to 31.1 mg (0.1 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 0,91 ml of 1 N HCI and mix from 8.1 mg (0.1 mmol) of potassium cyanate. To the mixture add a few drops of methanol and stirred for 10 hours at a temperature of 50°C. the Crystals are separated and washed with water and simple e is Il.

Yield: 16 mg (45.1% of theory) of the product

Mass spectrum: the desired molar mass: 354, found [M+H]+=355,1.

Example 11

N-(2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}ethyl)-N'-metalmachine

to 62.2 mg (0.2 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 0.4 ml of DMF and mixed with 11.4 mg (0.2 mmol) of methylisocyanate at room temperature. The resulting mixture is stirred over night, filtered and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile + 0.1% of triperoxonane acid

B = water +0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 45,9 mg (62.3% of theory) of the product

Mass spectrum: the desired molar mass: 368, found [M+H]+=369,2.

Example 12

N-(2-{[6-amino-3,5-dicyano-4-(4-hydroxyphenyl)-2-pyridinyl]sulfonyl}ethyl)-N'-metalmachine

to 62.2 mg (0.2 mmol) 2-amino-6-[(2-amino-ethyl)sulfanyl]-4-(4-hydroxyphenyl)for 3,5-pyridineacetonitrile suspended in 0.4 ml of DMF and mixed with 14.2 mg (0.2 mmol) utilizationof at room temperature. P is obtained the mixture is stirred over night, filtered and purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 37,6 mg (49,2% of theory) of the product

Mass spectrum: the desired molar mass: 382, found [M+H]+=383,2.

Example 13

3,5-dicyano-4-(3,5-dichloro-4-hydroxyphenyl)-2-carbamoylmethyl-6-aminopyridine

337,2 mg (1 mmol) 2-amino-4-(3,5-dichloro-4-hydroxyphenyl)-6-effect-free remedy 3.5-pyridineacetonitrile and 207 mg (1.5 mmol) of bromoacetamide dissolved in 4 ml of DMF, mixed with 336 mg (4 mmol) of NaHCO3and stirred for 8 hours at KT. The mixture is diluted with water and washed with complex ethyl ester of acetic acid. The aqueous phase is acidified with 1N HCL, the resulting crystals are separated and dried.

Yield: 180 mg (45,7% of theory) of the product

Mass spectrum: the desired molar mass: 393, found [M+H]+=394,1.

Example 14

2-[(6-amino-3,5-dicyano-4-{4-[(4-methylpiperazin)sulfanyl]phenyl}-2-pyridinyl)sulfonyl]ndimethylacetamide

84 mg (0,163 mmol) salt 2-amino-4-{4-[(4-methylpiperazine)sulfanyl]phenyl}-6-su who hanil-3,5-pyridinedicarboxylic-N-methylmorpholine mix together with 53.3 per mg (0,244 mmol) bromoacetamide and 54.7 mg (of 0.65 mmol) and NaHCO 3in 0.5 ml of DMF overnight. After filtering the reaction solution is pre-purified preparative GHUR. Isolated fraction is evaporated in vacuum, the residue is purified preparative thin-layer chromatography.

Yield: 14 mg (18,2% of theory) of the product

Mass spectrum: the desired molar mass: 471, found [M+H]+=472,1.

Example 15

2-[{6-amino-3,5-dicyano-4-[-(piperidinomethyl)phenyl]-2-pyridinyl}-sulfanyl)ndimethylacetamide

82 mg (0,164 mmol) salt 2-amino-4-[4-(piperidinomethyl)phenyl}-6-effect-free remedy Z-pyridinedicarboxylic-M-methylmorpholine mix together with a 53.5 mg (0,246 mmol) bromoacetamide and 55 mg (of 0.65 mmol) and NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution was purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile + 0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 42,8 mg (57,2% of theory) of the product

NMR [400 MHz, DMSO-d6]: 1.4 m (2H), 1.6 m (4H), 3.0 (4H), 3,9 (2H), 7,25 (1H), 7.5 C (1H), 7.8 (2H), 7.9 (2H), 8.1 d wide (2N).

Example 16

2-[{6-amino-3,5-dicyano-4-[-(morpholinoethyl)Fe is Il]-2-pyridinyl}-sulfanyl)ndimethylacetamide

90 mg (0,179 mmol) salt 2-amino-4-{4-(morpholinomethyl)phenyl}-6-effect-free remedy 3,5-pyridinedicarboxylic-N-methylmorpholine mix together from 58.5 mg (0,269 mmol) bromoacetamide and 60 mg (0.71 mmol) of NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution was purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water +0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 43,7 mg (53.2% of theory) of the product

NMR [400 MHz, DMSO-d6]: 2,9 Tr (4H), 3,65 Tr (4H), 3,9 (2H), 7,25 (1H), 7.5 C (1H), a 7.85 (2H), 7.95 is d (2N), 8,15 d wide (2N).

Example 17

2-(4-{2-amino-6-[(2-amino-2-oxoethyl)sulfanyl]for 3,5-dicyano-4-pyridinyl}-phenoxy)acetic acid

135 mg (0,316 mmol) salt 2-(4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)phenoxy]-acetic acid-N-methylmorpholine mix together from 103.3 mg (0,474 mmol) bromoacetamide and 106,1 mg (1,263 mmol) and NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution is pre-purified preparative GHUR. Isolated fraction is evaporated in vacuum, the mod is to cleanse preparative thin-layer chromatography.

Yield: 14 mg (11.6% of theory) of the product

Mass spectrum: the desired molar mass: 383, found [M+H]+=406,2.

Example 18

4-{2-amino-6-[(2-amino-2-oxoethyl)sulfanyl]for 3,5-dicyano-4-pyridinyl}-benzoic acid

72 mg (0.18 mmol) salt 2-[4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)phenoxy]-acetic acid-N-methylmorpholine mixed with a 59.2 mg (0.27 mmol) of bromoacetamide and 60.9 mg (0,72 mmol) and NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution is pre-purified preparative GHUR. Isolated fraction is evaporated in vacuum, the residue is purified preparative thin-layer chromatography.

Yield: 11 mg (17.2% of theory) of the product

Mass spectrum: the desired molar mass: 353, found [M+H]+=353,9.

Example 19

4-{2-amino-6-[(2-amino-2-oxoethyl)sulfanyl]for 3,5-dicyano-4-pyridinyl}-methylbenzoate

89 mg (0,216 mmol) salt of 4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)-complex methyl ester benzoic acid-N-methylmorpholine mixed with 70,7 mg (0,324 mmol) bromoacetamide and 72.7 mg (0.86 mmol) of NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution was purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

The speed pot is ka: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 40,4 mg (50,8% of theory) of the product

NMR [400 MHz, DMSO-d6]: 3,9 (2H), 7,25 (1H), 7.5 C (1H), 7.7 (2H), 8.1 (2H),8,1 with a wide (2N).

Example 20

2-({4-[4-acetylamino)phenyl]-6-amino-3,5-dicyano-2-pyridinyl}sulfanyl)ndimethylacetamide

44 mg (0.11 mmol) of the salt of N-[4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)phenyl]-ndimethylacetamide-N-methylmorpholine mixed with 35 mg (0.16 mmol) of bromoacetamide and 36 mg (0.43 mmol) of NaHCO3in 0.5 ml of DMF overnight. After filtering the reaction solution was purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 400 μl of DMF solution

Output: 18,3 mg (46.6% of theory) of the product

NMR [400 MHz, DMSO-d6]: 2,1 s (3H), 3,9 (2H), 7,25 (1H), 7.5 (3H), 7.7 (2H), 8,0 wide (2N), of 10.25 (1H).

Example 21

2-Amino-6-[(2-hydroxyethyl)sulfanyl-4-(4-hydroxyphenyl)for 3,5-pyridinedicarboxylic

and 26.8 mg (0.1 mmol) 2-amino-4-(4-hydroxyphenyl)-6-effect-free remedy 3.5-pyridineacetonitrile dissolved in 0.2 ml dimethylformamide. Then to the mixture is added 20 mg (0,238 mmol) of solid sodium bicarbonate and the solution 18,74 mg (0.15 mmol) 2-bromoethanol 0.06 ml of dimethylformamide.

The reaction mixture was shaken overnight, and after filtration purified preparative GHUR.

Conditions GHUR:

Column: GROM-SIL 120 ODS-4 NO 5 MK 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 1,75 min 10% A; for 5.5 min 90% A; 8 min 90% A; 8,1 min 10% A; 9 min 10% But

Volume of injection: 300 μl of DMSO solution

Holding time: 3,97 minutes

Output: a 14.1 mg (45.1% of theory) of the product

Mass spectrum: the desired molar mass: 312, found [M+H]+=313.

Example 22

1. Stage

N-[4-(2,2-dicyanovinyl)phenyl]ndimethylacetamide

of 32.6 g (0.2 mol) of 4-acetamidobenzaldehyde and 13,74 g (0,208 mole)of the nitrile of Malon put in 140 ml of ethanol and mixed with 24 drops of piperidine. The mixture is stirred for 30 min in the presence of phlegmy. After cooling, the crystals are separated and dried.

Output: 38,6 g (90.6% of theory) of the product

Mass spectrum: the desired molar mass: 211, found [M+H]+=212.

2. Stage

N-{4-2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}-ndimethylacetamide

19 g (0.09 mol) of N-[4-(2,2-dicyanovinyl)phenyl]acetamide", she 5,95 g (0.09 mole) of the nitrile of Malon and to 9.91 g (0.09 mol) of thiophenol placed in 120 ml of ethanol and mixed with 0.4 ml of triethylamine. The mixture is stirred for 30 min in the presence of phlegmy, and crystallization. After cooling, the product is separated and dried in vacuum.

Output: of 10.25 g (29,6% of theory) of the product

Mass spectrum: the desired molar mass: 385, found [M+H]+=386.

3. Stage

N-[4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)phenyl]-ndimethylacetamide

of 1.16 g (3 mmol) of N-{4-[2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}-ndimethylacetamide dissolved in 10 ml of DMF in the presence of argon, add 0,78 g (10 mmol) of sodium sulfide and stirred for 2 hours at a temperature of 80°C. the mixture is Then mixed with 20 ml of 1N HCl, the resulting crystals are separated and dried in vacuum.

Output: 428 mg (46,1% of theory) of the product

Mass spectrum: the desired molar mass: 309, found [M+H]+=310,1.

4. Stage

Triptorelin 2-[({4-[4-(acetylamino)phenyl]-6-amino-3,5-dicyano-2-pyridinyl}sulfanyl)-methyl]-1H-imidazolyl-1-FL

309 mg (1 mmol) N-[4-(2-amino-3,5-dicyano-6-effect-free remedy 4-pyridinyl)-phenyl]-ndimethylacetamide, 241 mg (1 mmol) of 2-(methyl bromide)-1H-imidazol-hydrobromide and 336 mg (4 mmol) of NaHCO3displacement is more in 2 ml of DMF at KT. After 2 hours the mixture is diluted with 4-5 ml of water, the resulting beige crystals separated and dried in vacuum. Crystals (310 mg) was dissolved in DMSO and purified preparative GHUR 9 injections. The appropriate fraction is evaporated in vacuo, the crystalline residue is suspended in water, separated and dried in vacuum.

Conditions GHUR:

Column: Kromasil 100 C18, 5 μm 50x20 mm

The primary column: GROM-SIL ODS 4 15 MK 10x20 mm

Wavelength: 220 nm

Flow rate: 25 ml/min

Gradient: A = acetonitrile +0.1% of triperoxonane acid

B = water + 0.1% of triperoxonane acid

0 min: 10% A; 2 min 10% A, 6 min 90% A; 7 min 90% A; and 7.1 min 10% A, 8 min 10% But

Volume of injection: 500 μl of DMSO solution

Holding time: 3,6 minutes

Output: 234 mg (60% of theory) of the product

Mass spectrum: the desired molar mass: 389, found [M+H]+=390,1.

1H-NMR [300 MHz, DMSO-d6]: δ=2,1 s (3H), 4,7 (1H), 7.4 (1H), 7,55 (1H),7,7D(2N),8,1 with a wide (2N), of 10.25 (1H), 14,2 with broad (1H).

The compounds listed in the tables below (examples 1 And 377 And 378 And 413 and 1 - 375) receive the same as the above methods. The identity and purity of the compounds is confirmed LC-MS.

The compounds of examples 1 And 413 or isolated in the form of crystals or if they are not crystallized directly from the reaction solution, purified preparative GHUR.

The compounds of examples 1 To 375 get in m is sstube 10 µmol the same as the above methods. Purification and identification of such compounds is conducted through a system of GHUR-MS.

In the following tables in the structures containing the group-N-, always refers to the group-NH-, and in the structures containing the group-N always refers to the group-NH2.

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)
A1325326of 57.5
A23263277,0
A332632752,7
A433934 67,5
A534034160,8

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)
A635435553,6
A736636730,0
A838638757,2
A939439512,2/td>
A10404405393

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)
A1141541658,2
A1243043125,1
A1344644728,1
A1445645729,6

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)
A1547047162,2
A1634234354,0
A1735235373,8
A1840240365,6

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)/td>
A1941641751,9
A2034134229,7
A2135435584,4
A2235535610,0
A2335535635,2

ExampleProductThe selected substance AndThe selected substance InThe desired Molar massFound [M+H]+Yield (% of theory)
A2436836977,1
A2536937070,9
A2635438468,1
A2739539660,2
A2841541658,0

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A29 42342431,2
A3043343436,2
A3144444551,1
A3245946046,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A3347547649,7
A34 48548647,1
A3549950064,0
A3650750837,5

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A3752152261,5
A3837137263,8
A39 38138250,3
A4043143240,8

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A4144544671,9
A4244544632,6
A4331231360,8
A44 32532678,4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A4532632713,9
A4632632717,8
A33934089,6
A48 motorway34034177,6
A 35435556,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A5036636747,5
A5138638736,5
A5239439520,5
A5340440558,8

td align="center"> The selected substance In
ExampleProductThe selected substance AndThe desired molar massFound [M+H]*Yield (% of theory)
A5441541618,3
A5543043129,8
A5644644742,2
A574564579,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A58 motorway 47847954,2
A59492493to 66.3
A6034234373,6
A6135235368,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A6240240341,2
A63 41641752,1
A41641752,6
A6531431562,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A6632732858,0
A6732832917,1
A68 32832953,9
A34134257,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A7034234335,6
A7135635749,7
A7236036143,3
A73 36836914,7
A74388389of 17.5

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A7541741831,1
A7645845919,5
A47247341,8
A480 48132,9

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A49449529,0
A8034434545,6
A8135435537,2
A8240440537,6

ExampleProductThe selected substance AndThe selected substance InSearched supposedly the RNA mass Found [M+H]*Yield (% of theory)
A8341841963,3
A84418419a 21.5
A8533133271,3
A8634434566,9
A8734534676,3

ExampleProductThe selected substance AndThe selected substance InThe desired molar massOn the experimental [M+H] *Yield (% of theory)
A88358359is 83.8
A8935936089,7
A9037337470,5
A9138538612,2
A9240540684,0

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]* Yield (% of theory)
A9341341412,1
A9442342423,6
9543443567,3
A9648848967,4
A9749649790,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Output (% Theo is AI)
A98 motorway51051155,7
A99361362103,1
A10037137248,3
A10142142297,9
A10243543651,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A10343543663,7
A10429629782,0
A10530931075,6
A10631031172,5
A10732332484,4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A108 32432567,8
A10933833971,8
A11034234344,7
A11135035118,5
A11237037173,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A113 37837946,8
A11438838991,4
A115399400of 17.5
A11641441516,7
A117430431of 31.4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A118 45445558,4
A11946246377,1
A12047647713,0
A12132632789,8

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A12233633769,3
A123 38638773,2
A12440040166,9
A12540040174,2
A12633133272,6

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A12734434568,1
A128 345346to 70.2
A12935835972,4
A13035936044,3

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A13137337457,7
A13237737817,2
A133 38538614,0
A1344054068,9

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A13541341417,2
A13642342412,8
A137434435the 10.1
A138 44844910,0

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A13947447552,1
A14048848952,3
A14149649750,2
A14251051143,5

ExampleProductThe selected substance AndThe selected substance In The desired molar massFound [M+H]*Yield (% of theory)
A14336136256,0
A1444354363,7
A14543543667,4
A14633133264,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A147 34434570,7
A14835835972,7
A14935936058,8
A15037337456,3

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A15137737855,5
A152 38538664,2
A15340540632,4
A15441341455,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A15542342453,9
A15643443574,9
A157448 44967,0
A15846446572,0

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A15947447573,0
A160488489to 75.2
A16149649775,5
A162510511 67,4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A163371372to 75.2
A16442142257,7
A16543543671,3
A16643543654,0

Found [M+H]*
ExampleProductThe selected substance AndThe selected substance InThe desired molar massYield (% of theory)
A16732632750,9
A16833934076,3
A16935335450,4
A17037237330,6

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A171 41841913,6
A17243043163,8
A17344444526,2
A17446046132,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A17547047196,9
A176484 48518,2
A17749249378,5
A17835635717,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A17936636731,1
A18041641780,0
A181430431 66,2
A18243043173,6

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A18331031128,4
A18432332439,3
A18532432541,9
A186337338of 40.9
ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A18733833911,5
A18835235329,2
A18935635751,9
A19036436577,4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massNai is i.i.d. [M+H] *Yield (% of theory)
A19141441551,8
A19242842958,2
A19344444558,2
A19445445529,5

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A195468 46943,8
A19647647751,7
A19749049173,9
A198340341of 37.9

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A19935035180,8
A200400401 48,4
A20141441520,7
A20241441561,0

td align="center"> A206
ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A20334134255,4
A20435435538,4
A20536836970,6
36937049,5

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A20738338465,5
A20839539614,2
A20941541622,9
A21043343440,8

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A211444445to 70.2
A21245946021,6
A213475476of 57.5

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A2144854861,5
A215499500to 43.1
A21650750856,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A21737137262,5
A21838138239,9
A21943143255,6
A44544632,6

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A22135235361,3
A222365366an 80.2
A22336636773,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H *Yield (% of theory)
A22437938081,7
A22538038171,0
A22639439565,9
A39839976,3

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A228407 40879,7
A22942742840,8
A23043443522,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A231444445the 9.7
A232456457the 15.6
A233470471 43,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A23448648771,1
A23549649796,4
A23651051184,6

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A237 51851941,7
A23853253328,8
A23938238383,7

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A240392393of 54.8
A24144344475,0
A242 45745850,2

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A24345745844,9
A24435235354,5
A24536937085,5
A37037160,7

ExampleProductThe selected substance AndThe selected substance In The desired molar massFound [M+H]*Yield (% of theory)
A24738438559,1
A24838638779,7
A24937037151,6
A37037149,4

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A251 44844970,4
A25242642739,0
A25332432566,9
A32832990,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A255341342114,5
A256 34234370,7
A25735635777,7
A37437587,1

ExampleProductThe selected substance AndThe selected substance InThe desired molar massFound [M+H]*Yield (% of theory)
A25934334385,3
A26034234373,3
A261419 420for 91.3
A39739866,2

ExampleProductThe molar. weight
B1419
B2465
B3439
B4465
B5450

ExampleProductThe molar. weight
B6455
V7435
B8498
B9419
B10 484

ExampleProductThe molar. weight
B11406
B12406
B13541
B14481
B15423

ExampleProductThe molar. weight
B16473
B17474
B18450
B19515
B20439

ExampleProductThe molar. weight
B21474
B22430
W434
In 24443
B25507

ExampleProductThe molar. weight
W406
27469
B28515
W540

ExampleProductThe molar. weight
B30476
W463
V32497
W461
B34 541

ExampleProductThe molar. weight
W562
W486
W473
W373

ExampleProductThe molar. weight
W434
In40560
B41 content433
W474

ExampleProductThe molar. weight
W451
B44515
W419
B46556

ExampleProductThe molar. weight
B47369
W631
W550
50492

ExampleProductThe molar. weight
W545
W515
W479
W484

ExampleProductThe molar. weight
W381
W527
W 417
W396

ExampleProductThe molar. weight
W397
B60460
W373
W415

ExampleProductThe molar. weight
W357
W400
B65384
W430

ExampleProductThe molar. weight
W430
W40
W400
70463

ExampleProductThe molar. weight
W384
W371
B73371
W371

ExampleProductThe molar. weight
W474
W388
W438
W415

ExampleProductThe molar. weight
W408
B8 473
W371
W434

ExampleProductThe molar. weight
W481
W442
W428
W463

ExampleProductThe molar. weight
W528
W452
W438
W338

ExampleProductThe molar. weight
W 399
B92398
W417
W481

ExampleProductThe molar. weight
B95384
B96334
W516
W457

ExampleProductThe molar. weight
99481
B100445
W399
W456

ExampleProductThe molar. Mac is and
103346
W382
W361
W362

ExampleProductThe molar. weight
W426
W338
W380
W322

ExampleProductThe molar. weight
W379
W435
W419
W465

ExampleProductThe molar. weight
W465
W498
W419
W406

ExampleProductThe molar. weight
W406
W406
W481
W423

ExampleProductThe molar. weight
W473
W450
W443
W 507

ExampleProductThe molar. weight
W469
W515
W476
W562

ExampleProductThe molar. weight
W486
W473
W373
W434

ExampleProductThe molar. weight
W451
W515
B137415
W419

ExampleProductThe molar. weight
W369
W492
W484
W427

ExampleProductThe molar. weight
W381
W417
W396
W397

ExampleProductThe molar. weight
W460
W373
W 357
W414
B151416

ExampleProductThe molar. weight
W416
W416
W444
W453

ExampleProductThe molar. weight
W550
W573
W444
W462

ExampleProductThe molar. weight
W 425
W494
W602
W391

ExampleProductThe molar. weight
W427
W407
W471
W424

ExampleProductThe molar. weight
W430
W461
W435
W461

ExampleProductThe molar mass
W445
W451
W430
W430

ExampleProductThe molar. weight
W493
W414
W401
W401

ExampleProductThe molar. weight
W401
W477
W418
W468

ExampleProductThe molar. weight
W469
W445
W435
W425

ExampleProductThe molar. weight
W430
W439
W503
W401

ExampleProductThe molar. weight
W425
W464
W511
W 472

ExampleProductThe molar. weight
W458
W493
W457
W558

ExampleProductThe molar. weight
W482
W468
W368
W430

ExampleProductThe molar. weight
W429
W469
W447
W511

ExampleProductThe molar. weight
W364
W546
W487
W475

ExampleProductThe molar. weight
W480
W493
W479
W423

ExampleProductThe molar. weight
W429
W486
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W376

ExampleProductThe molar. weight
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W391
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ExampleProductThe molar. weight
W410
W352
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W457

ExampleProductThe molar. weight
W441
W 487
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ExampleProductThe molar. weight
W457
W441
W427
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ExampleProductThe molar. weight
W427
W503
W444
W494

ExampleProductThe molar. weight
W 471
W456
W465
W529

ExampleProductThe molar. weight
W427
W490
W498
W485

ExampleProductThe molar. weight
W519
W584
W456
W455

ExampleProductThe molar. weight
W473
W537
W441

ExampleProductThe molar. weight
W390
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W513

ExampleProductThe molar. weight
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